The overarching aim of Project-2 is the completion of an observational study (n = 3000) designed to test the P50-developed adaptive pharmacotherapy algorithm within the ?Translational Smoking Cessation Program? (TSCP). During the past four years of P50 funding we have developed a pharmacotherapy ?Algorithm? that uses response to nicotine ?Test-Patch,? together with dependence testing, to allocate smokers to specific pharmacotherapies. Aim 1. The study will randomize 30 Duke University clinics participating in the Translational Smoking Cessation Program (TSCP) to Algorithm-based pharmacotherapy or Varenicline. After recruitment of 1500 (50%) subjects, the randomization status of clinics will be reversed (crossover design), allowing for control of both clinic effects and order effects. We hypothesize 1) that smokers treated in the TSCP with Algorithm-based pharmacotherapy vs. Varenicline will show significantly higher biochemically confirmed 12-week post-quit 30-day continuous abstinence (primary study outcome), and 2) that Algorithm-based pharmacotherapy compared to Varenicline will show significantly higher self-reported abstinence at 26- and 52-week post-quit. Aim 2. We hypothesize 1) that medication non-adherence will be significantly lower in Algorithm vs. Varenicline treatment group, 2) that these differences will be greatest among low-income subjects, and 3) that within the Patch Non-Responder Algorithm arms, abstinence rates will be higher among subjects opting for the High- vs. Low-Intensity Behavioral Intervention. Aim 3. We hypothesize 1) that a prospective economic analysis of Algorithm vs. Varenicline-based pharmacotherapy will show significant improvement in cost-benefit outcomes from the perspective of smokers, healthcare systems, insurance companies, and employers and 2) that of TSCP implementation and operations will show favorable cost- benefit outcomes for long-term operation.